Field of the Invention
The present invention relates to the field of determining the sensitivity of an individual to a toxicant. In particular, it relates to the method of determining the sensitivity of an individual to low-dose ionizing radiation.
Description of Related Art
Ionizing radiation is an established human carcinogen. The widespread use of advanced radiological imaging, such as X-ray computed tomography scans (CT-scans), raises a concern about the potential danger of exposure to low-dose ionizing radiation (LDIR). Humans are likely to have variable responses to LDIR and therefore, medical exposure to LDIR may produce different effects depending on individual predisposition. For example, a familial history of cancer has been identified as a modifying factor of cancer risk associated with diagnostic radiation response. However, quantitative measures of an individual response to LDIR have not been developed. Studying the variability of responses to LDIR in human population or specific sub-groups cannot be done by direct experimentation. Therefore, donor-derived substances (body fluids, genetic material, or cells) have been used to gain an understanding on what predisposes a person to radiation-related diseases. Traditionally, peripheral blood lymphocytes have been used to study the differences in individual responses to ionizing radiation and LDIR in particular. These studies confirmed that individuals differ in their response to LDIR. However, the utility of these findings is hampered by low-proliferation potential of the primary lymphocyte cultures, low signal-to-noise ratio, and transience of the measured response indicators, such as DNA-damage response or oxidative stress.
Despite the alarming findings that LDIR from medical procedures increases the risk of various cancers, medical LDIR exposure in the U.S. remains one of the most prevalent risk factors for cancer, especially breast cancer. Such an exposure to LDIR has increased in the U.S. significantly due to the recent wide spread use of CT-scans. CT-scans are within the range of low-dose (i.e., <0.5 Gy) but involve much greater (in an order of magnitude) ionizing radiation doses as compared to other X-ray procedures. Accordingly, the carcinogenic risk posed by CT-scans may be significant. For example, it has been estimated that approximately 29,000 cancers could be related to CT-scans performed in the U.S. during the year of 2007 alone. In fact, the majority of these cases, i.e. two-thirds, were projected to occur in women based on higher frequency of CT-scans among women and the high risk associated with breast cancer. Other harmful effects of LDIR include increased risk of circulatory, respiratory, and digestive diseases. Thus, CT-scans currently present an important risk factor for cancer and several non-cancer outcomes.
Endothelial colony forming cells, or ECFCs, are a type of progenitor cell that was first identified by Ashahara and colleagues as mononuclear peripheral blood fraction-derived CD34-positive and CD45-negative cells that form colonies in cell culture. The main feature of ECFC is their visible appearance in a culture dish as single colonies of cobblestone-looking cells. ECFCs are called “late outgrowth endothelial cells” because they “appear” 1-3 weeks after the initial seeding on a culture dish of either a whole blood or mononuclear cell fraction of the blood. The most important features identified by the researchers in the field are the robust clonal growth and expression of a variety of cell surface markers characteristic to arterial and venous endothelial cells, and a restriction to the endothelial lineage during differentiation. In addition, ECFCs form capillary-like structures in vitro and capillary plexus in collagen, type I (plus fibronectin) gel plugs implanted in immunodeficient mice. Overall, ECFCs appear to display properties characteristic to endothelial progenitor cells.
Mesenchymal stem cells (MSC) are multipotent progenitor cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, and muscle. It has been proposed that a cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology and can undergo osteogenic, adipogenic and chondrogenic differentiation ex-vivo. Nevertheless, the cultured MSCs, like ECFCs express on their surface CD34, CD73, CD90 and CD105, while both cell types lack the expression of most lineage-specific markers.
It would be useful therefore to have a means for the determination of the risk of an individual to the exposure to LDIR in a given individual especially in a clinical setting. If a person was determined more sensitive, the individual could in combination with their doctor determine the risk of using CT-scans or other procedures involving LDIR or the like.